Abstract

Atrial fibrillation (AF) has been found to occur with an increased frequency in patients with malignancies, particularly in those undergoing cancer surgery. The occurrence of AF in cancer may be related to comorbid states or a direct tumor effect or may represent a complication of cancer surgical or medical therapy, whereas inflammation may be a common denominator for both conditions. Treating AF in patients with malignancies is a challenge, especially in terms of antithrombotic therapy, because cancer may result in an increased risk of either thrombosis or hemorrhage and an unpredictable anticoagulation response, whereas thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) may not be applicable. The general lack of evidence imposes an individualized approach to the management of AF in those patients, although some general recommendations based on current guidelines in noncancer patients and the existing evidence in cancer patients, where available, may be outlined.

Atrial fibrillation (AF) is the most common sustained arrhythmia; it affects 1.5% to 2% of the general population, and this prevalence increases to 10% at 80 years of age and to 18% at 85 years of age (1,2). In addition to aging, several cardiovascular conditions, such as hypertension, heart failure, and valvular disease, as well as noncardiovascular conditions, such as chronic pulmonary disease, diabetes, electrolyte abnormalities, thyroid dysfunction, and chronic kidney disease, predispose to the development of AF (2). Given the increasing occurrence of malignancies in the elderly and the coexistence of other conditions predisposing to AF in cancer patients, an association between those 2 conditions would be expected. On the other hand, AF confers an increased risk of cardiovascular complications, including a 5-fold risk of stroke and a 3-fold risk of heart failure, as well as a doubled mortality rate (1). Therefore, AF may present an additional factor affecting the prognosis of malignant diseases and a challenge for the therapeutic management of cancer patients.

Epidemiology

The bulk of epidemiological evidence on the association between AF and cancer is generally limited, with the exception of AF after cancer surgery (Table 1). A large epidemiological study on 24,125 patients with newly diagnosed cancer recently shed some new light on the issue. More specifically, the prevalence of AF at baseline (i.e., at cancer diagnosis) was 2.4% (baseline AF), whereas AF developed in another 1.8% of patients after the diagnosis of cancer (new-onset AF) (3). In this study, new-onset AF was associated with a 2-fold risk of thromboembolism and a 6-fold risk of heart failure, even after adjustment for known risk factors (adjusted hazard ratios [HRs]: 1.98 [p < 0.001] and 6.3 [p < 0.001], respectively) (3).

The inverse approach was followed by another large population-based cohort that compared the prevalence of colorectal cancer in patients with and without AF. The authors compared 28,333 patients with AF with 283,260 matched individuals without AF; the prevalence of colorectal cancer was 0.59% in AF patients and only 0.05% in those without AF (HR: 11.8) (4). Furthermore, in a cohort of 2,339 patients admitted for surgery, AF was present with at least twice the frequency in patients admitted with a first diagnosis of colorectal or breast cancer than in those admitted for nonneoplastic surgery (3.6% vs. 1.6%) (5). In another study from the same group, patients with a first diagnosis of colorectal cancer had an approximately 3-fold higher risk of AF compared with patients admitted for nonneoplastic diseases (HR: 3.5) (6).

The most frequent form of cancer-related AF is that occurring post-operatively (Table 1). AF is particularly frequent during thoracic surgery, especially pulmonary resection for lung cancer, an association that has been reported since the early 1970s (7). In a large cohort of 13,906 patients who underwent lung cancer surgery, AF occurred post-operatively in 12.6% of cases (8). Other studies in patients subjected to lung cancer surgery reported incidences ranging between 6% and 32% (9–16), whereas a single study on a small population reported an incidence as high as 60% (17). Furthermore, post-operative AF has been reported in 4.4% of 563 patients who underwent elective colectomy for colorectal cancer (18), as well as in 9.2% of 207 patients who underwent esophagectomy for esophageal cancer (19). Post-operative AF seems to have a negative impact on patients' prognosis. Thus, AF occurring during lung cancer surgery increased post-operative mortality (6.7% vs. 1.0% in patients without AF; p = 0.024), hospital length of stay, and intensive care unit admissions, and it was further associated with an almost 4-fold higher long-term mortality in 5-year survivors after adjustment for other risk factors (HR: 3.75; p = 0.007) (9). Whether there is a significant difference concerning post-operative AF in cancer patients compared with noncancer patients undergoing similar surgical procedures is not easy to conclude on the basis of the available evidence. A direct comparison is not available, whereas a comparison on the basis of the results of different studies is not possible given that AF prevalence is affected by and therefore should be adjusted for several factors. A single large-scale retrospective observational study involving 370,447 patients undergoing major noncardiac surgery reported a 3% incidence of post-operative AF, with considerable variation by race and type of surgery, but provided no data on the impact of cancer surgery (19). On the other hand, post-operative AF complicates ∼25% to 30% of patients undergoing cardiac surgery such as coronary artery bypass grafting or valve surgery (20,21). However, these latter patients have established heart disease and undergo a procedure that involves direct manipulation of cardiac tissues, and therefore AF occurrence is expected to be high (19). The available evidence on the risk factors for the development of post-operative AF in cancer patients is outlined in Table 2.

Risk Factors for the Development of Post-Operative Atrial Fibrillation in Patients With Cancer

In contrast to the aforementioned studies, there is some evidence, derived by rather small study populations, arguing against the association between AF and cancer or the impact of AF on the prognosis of cancer patients (22). Thus, cancer was not an independent predictor of atrial arrhythmias in a cohort of 131 patients, whereas AF was not an independent predictor of survival in 175 patients with colorectal cancer (23,24). Sample size and the type and severity of cancer in previous analyses represent important factors that may account for the lack of data consistency. Another essential issue is the methodology of AF detection followed in different studies (i.e., symptoms driven, electrocardiographic monitoring) that may have crucially affected the reported frequency.

Pathophysiology

AF in cancer patients may represent a comorbid state because those patients share several factors predisposing to AF such as advanced age, electrolyte abnormalities, hypoxia, and metabolic disorders (22,25,26). The autonomic nervous system imbalance due to the increased sympathetic drive caused by pain or other forms of physical or emotional stress may also predispose to AF (27). AF may further result from paraneoplastic conditions including hyperparathyroidism and autoimmune reactions against atrial structures (27). AF may also represent a direct manifestation of the neoplasm in the case of primary or metastatic cardiac tumors or tumors of adjacent tissues such as the lungs and esophagus that invade the heart. Moreover, AF may be a complication of cancer therapy. As previously stated, post-operative AF occurs frequently, particularly in the case of pulmonary resection. In addition, several drugs used for the treatment of cancer have been found to induce AF (22,28–32). These drugs include most of the cytotoxic agents such as cisplatin, 5-fluorouracil, doxorubicin, paclitaxel/docetaxel, ifosfamide, gemcitabine, and mitoxantrone; high-dose corticosteroids; antiemetic agents such as ondansetron; targeted therapies; and bisphosphonates (22,28–33). A single study, however, argued against biphosphonate related-AF (35).

Inflammation may be a common denominator of both conditions. It has been suggested that AF may actually represent an inflammatory complication of cancer (25). In a population-based study in 5,806 subjects followed for a median of 7.8 years, C-reactive protein (CRP) increase was associated both with the presence of AF at baseline (odds ratio for fourth vs. first CRP quartile: 1.8) and with future AF development (HR for fourth vs. first CRP quartile: 1.3) (34). An increase in CRP and other inflammatory markers such as tumor necrosis factor-α and interleukins 2, 6, and 8 has been found in AF (23,35), although an increased neutrophil count was associated with the occurrence of postoperative AF in patients who underwent surgery for colorectal cancer (18).

Overall, the underlying mechanisms of AF induction in cancer patients are poorly understood and remain to be elucidated by future research. An overview of the potential pathogenetic links between cancer and AF is outlined in Figure 1.

An Overview of the Potential Pathogenetic Mechanisms Linking Cancer With Atrial Fibrillation

Cancer may cause atrial fibrillation, rarely by direct invasion of the heart and more commonly by chemotherapy and supportive therapies, surgery, chronic inflammation, autonomous nervous system (ANS) imbalance, paraneoplastic manifestation, and metabolic, electrolyte, and other abnormalities. In addition, aging and coexisting comorbid conditions may predispose both to cancer and to atrial fibrillation.

Treatment

Treatment of AF in cancer patients is a challenge, particularly in terms of antithrombotic therapy for stroke prevention. On the one hand, cancer is itself a prothrombotic state, thus further increasing the risk of thromboembolic events in patients with AF. Despite that, the history of cancer has not been incorporated in the thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) or CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 [doubled], diabetes, stroke [doubled]–vascular disease, age 65 to 74, sex [female]) that are currently suggested to be used to guide antithrombotic therapy (1,2). Moreover, some anticancer therapies and in particular the novel angiogenesis inhibitors have been related to thromboembolic complications (32). On the other hand, some malignancies, such as primary or metastatic intracranial tumors and hematological malignancies, pose an increased risk of hemorrhage. To complicate things further, the response to anticoagulation may not be predictable owing to the concomitant medication or metabolic disorders associated with cancer (36). Actually, the use of vitamin K antagonists for deep venous thrombosis in patients with malignancies was associated with a 6-fold higher risk of hemorrhage compared with patients without cancer (37). In addition, there is practically no evidence to guide practice, and the recent randomized clinical trials on the novel anticoagulants dabigatran, rivaroxaban, and apixaban for stroke prevention in AF did not include cancer patients (38–40). Finally, using the established thromboembolic risk prediction scores to guide antithrombotic therapy in cancer patients may not be adequate. More specifically, in a large cohort of 24,125 patients with newly diagnosed cancer, although the CHADS2 score was predictive of thromboembolism risk in patients with baseline AF, it did not predict thromboembolic events in those with new-onset AF (i.e., AF that occurred after cancer diagnosis) (3). Therefore, the decision regarding the initiation of antithrombotic therapy in cancer patients has to be strictly individualized, weighing cautiously the benefits against the risks according to the features of each particular patient.

Low molecular weight heparin (LMWH) may have a more favorable outcome than vitamin K inhibitors in patients with malignancies. Actually, dalteparin was associated with better survival than coumarin derivatives in patients with nonmetastatic solid tumors and venous thromboembolism (41). This may be related to the potential antitumor and antimetastatic effects of LMWH that have been shown to provide a survival benefit in patients with different types of cancer (42,43). As a result, the American College of Chest Physicians recommended the use of LMWH over vitamin K antagonists in cancer patients with venous thromboembolism (44). The role of LMWH in long-term anticoagulation therapy of patients with cancer and AF remains to be proven.

The decision regarding whether to begin antiarrhythmic therapy may also be difficult in cancer patients. In several cases, restoration and maintenance of sinus rhythm are necessary due to contraindications to long-term antithrombotic therapy. On the other hand, the antiarrhythmic medications that are effective in rhythm control, such as class III drugs, are associated with QT interval prolongation. Prolongation of the QT interval may also result from several drugs used in the treatment of cancer, including chemotherapeutic agents such as arsenic trioxide, targeted therapies such as angiogenic inhibitors, and supportive therapies such as ondansetron (45–47). Concomitant conditions such as electrolyte disturbances that occur frequently in these patients may also have a proarrhythmic effect. Clinical evidence in this field is quite limited. A retrospective analysis of 81 cancer patients who received ibutilide for cardioversion of AF or atrial flutter at MD Anderson Cancer Center showed that the drug was effective in 75% of cases (48). In the same study, although 84% of patients received at least 1 additional drug associated with QT interval prolongation, no changes in corrected QT interval were encountered in any of the patients. Radiofrequency catheter ablation for pulmonary vein isolation has not yet been studied in cancer patients, and it may be a good option for some of these patients, particularly when rhythm control therapy has failed or there are concerns about its interaction with the background therapy (49). Nevertheless, there are several issues that need to be taken into consideration when considering this technique for cancer patients, such as the high doses of anticoagulation required during the procedure and the risk of trauma in cancer patients with a high bleeding risk or the risk of thromboembolism associated with placing intracardiac catheters in those patients with a prothrombotic tendency. Given the lack of evidence of a specific rhythm- or rate-control strategy in cancer patients with AF, the strategy followed in other chronic conditions such as heart failure may be followed, with particular attention to concomitant or planned anticancer therapies and comorbid conditions (50,51).

The management of post-operative AF represents an additional challenge given its high occurrence rate, especially during surgery for lung cancer, as previously stated. Postoperative N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels may identify patients at increased risk of post-operative AF and thus guide the use of prophylactic antiarrhythmic therapy (10). More specifically, in patients undergoing thoracic surgery for lung cancer, increased NT-proBNP, according to the assay's age-related cutoffs, either 24 h before or 1 h after surgery, was associated with a substantially higher rate of AF (64% vs. 5% in patients without increased NT-proBNP; p < 0.001) (10). Another study identified a cutoff post-operative NT-proBNP level of 182 ng/l for the prediction of post-operative AF (14), whereas a B-type natriuretic peptide level of 30 pg/ml had a high specificity of 93% for predicting AF after pulmonary resection for lung cancer (52). In addition to natriuretic peptide level, echocardiographic indexes may also be useful, particularly those indicating left ventricular diastolic dysfunction or increased left ventricular diastolic pressures. A mitral E/e′ ratio >8 was highly sensitive (90% sensitivity) for predicting post-operative AF (16). Other predictors of post-operative AF include advanced age, male sex, long duration of surgery, advanced cancer stage, occurrence of surgical complications, need for post-operative blood transfusions, and history of hypertension and pre-operative paroxysmal AF (8,9,11,18).

Several drugs have been studied for the prevention or management of post-operative AF, mostly in patients undergoing cardiac surgery (Table 3). These agents included beta-blockers such as metoprolol and landiolol, statins, angiotensin-converting enzyme inhibitors, omega-3 fatty acids, and ranolazine (21,53–56). The corresponding data on cancer patients are limited. Post-operative amiodarone prophylaxis, given at 300 mg intravenously over 20 min immediately after surgery followed by 600 mg orally twice daily for 5 days, reduced the risk of AF by 23% in patients undergoing lung cancer surgery (12). A cost analysis of this trial showed that amiodarone was a cost-neutral way to prevent post-operative AF in lung cancer patients (57). Furthermore, landiolol, a novel, ultrashort-acting beta-blocker, when given in a small group of patients who experienced AF after elective pulmonary resection for lung cancer, accomplished a more profound perioperative reduction of heart rate and a quicker restoration of sinus rhythm compared with historical controls treated with verapamil and digoxin (13). In another small clinical trial, low-dose human atrial natriuretic peptide infusion during lung cancer surgery was protective against post-operative AF in patients with pre-operative B-type natriuretic peptide increase (≥30 pg/ml) (17). In 2 subsequent studies from the same group, human atrial natriuretic peptide effectively reduced the incidence of post-operative cardiopulmonary complications during lung cancer surgery in patients ≥75 years of age as well as in patients with chronic obstructive pulmonary disease (58,59). In contrast, acebutolol induced a nonsignificant reduction in the incidence of post-operative AF in patients undergoing pulmonary resection compared with diltiazem or placebo (60).

Studies on the Prevention or Treatment of Post-Operative AF in Patients With Cancer

Conclusions and Practical Considerations

The accumulated evidence suggests that a large part of AF in cancer patients results from surgery (4). The presence of AF may affect patients' prognosis, whereas its management, particularly in terms of antithrombotic therapy for stroke prevention, is a challenge. There are several issues that need to be addressed by future research concerning epidemiology, pathogenesis, diagnosis, prevention, and treatment, as outlined in Table 4.

Given the lack of evidence, there are currently no specific guidelines for AF therapy in patients with malignancies. An approach to practical issues concerning AF management based on the current guidelines in noncancer patients (1,61) and the existing evidence in cancer patients, where available, is shown in Table 5. In what concerns antithrombotic therapy in particular, certain features like intracranial tumors, chemotherapy-induced thrombocytopenia, and coagulation defects due to hematological malignancies may predispose to bleeding and therefore may constitute contraindications to antithrombotic therapy, even in patients at high thromboembolic risk. On the other hand, certain malignant tumors such as pancreatic, ovarian, lung, and primary hepatic cancer are associated with an increased thromboembolic risk, and the same applies to several chemotherapeutic agents such as cisplatin, gemcitabine, and 5-fluorouracil and supportive therapies like erythropoietin and granulocyte-colony stimulating factors (62–64). As a result, antithrombotic prophylaxis may be needed even in patients classified as low risk by risk assessment tools such as CHA2DS2-VASc score or others. An algorithm for antithrombotic therapy in cancer-related AF based on cancer features and established thromboembolic and bleeding risk assessment tools (CHA2DS2-VASc and HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (age >65 years), Drugs/alcohol concomitantly], respectively) is proposed in Figure 2. It should be stressed that the particular clinical features of cancer patients render an individually tailored therapy even more crucial, especially for antithrombotic prophylaxis.

Practical Recommendations for the Screening and Management of Cancer-Related AF on the Basis of Current Guidelines in Noncancer Patients and the Existing Evidence, Where Available, in Cancer Patients

Footnotes

This paper was partly supported by a grant from the Hellenic Cardiological Society. Dr. Farmakis is a member of the Steering Committee for a trial sponsored by Boehringer-Ingelheim Ellas. Dr. Parissis has received research grants from Abbott USA and ORION Pharma for heart failure; and has received honoraria from Servier International and Menarini International for lectures. Dr. Filippatos is a member of the Steering Committee for trials sponsored by Bayer and Corthera.

(2000) Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol18:3078–3083.

(2012) Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Eur J Heart Fail14:681–695.

(2013) Comparative efficacy and usefulness of acebutolol and diltiazem for the prevention of atrial fibrillation during perioperative time in patients undergoing pulmonary resection. Thorac Cardiovasc Surg61:365–372.

(2013) Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol61:1935–1944.

Toolbox

Thank you for your interest in spreading the word about JACC: Journal of the American College of CardiologyNOTE: We request your email address only as a reference for the recipient. We do not save email addresses.

Your Email *

Your Name *

Send To *

Enter multiple addresses on separate lines or separate them with commas.